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Skeletal muscle laminin and MDC1A: pathogenesis and treatment strategies.

Gawlik KI, Durbeej M - Skelet Muscle (2011)

Bottom Line: By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events.Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death.In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.

ABSTRACT
Laminin-211 is a cell-adhesion molecule that is strongly expressed in the basement membrane of skeletal muscle. By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events. The importance of laminin-211 in skeletal muscle is evident from merosin-deficient congenital muscular dystrophy type 1A (MDC1A), in which absence of the α2 chain of laminin-211 leads to skeletal muscle dysfunction. MDC1A is the commonest form of congenital muscular dystrophy in the European population. Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death. Mice with laminin α2 chain deficiency have analogous phenotypes, and are reliable models for studies of disease mechanisms and potential therapeutic approaches. In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions. We will also discuss the molecular pathogenesis of MDC1A and advances toward the development of treatment.

No MeSH data available.


Related in: MedlinePlus

Scheme of laminin-211 heterotrimeric structure. Laminin α2 chain is depicted in red, β1 in green and γ1 in blue. Laminin α2 chain consists of: the N terminal globular domain (LN); tandem rod domains of epidermal growth factor (LEa, LEb, LEc), separating the LN, L4a and L4b globular domains; the laminin coiled-coil (LCC) domain that tangles with the LCC domains of the β1 and γ1 chains; and the C-terminal laminin globular (LG) domains.
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Figure 1: Scheme of laminin-211 heterotrimeric structure. Laminin α2 chain is depicted in red, β1 in green and γ1 in blue. Laminin α2 chain consists of: the N terminal globular domain (LN); tandem rod domains of epidermal growth factor (LEa, LEb, LEc), separating the LN, L4a and L4b globular domains; the laminin coiled-coil (LCC) domain that tangles with the LCC domains of the β1 and γ1 chains; and the C-terminal laminin globular (LG) domains.

Mentions: The basement membrane is a thin scaffold of specific extracellular protein networks associated with various cell types, including muscle fibers. This specialized framework of extracellular matrix (ECM) provides important functional cues to cells. Laminins comprise a family of glycoproteins that are major components of all basement membranes [1]. Occurrence of a laminin molecule in hydra, one of the oldest multicellular organisms, indicates that laminins existed already 600 million years ago [2]. Laminins are large (400-900 kDa) heterotrimeric molecules composed of one α, one β and one γ subunit in a cruciform or T-shaped appearance. To date, five α, three β and three γ chains have been characterized. They represent the products of distinct genes that evolved by duplication and recombination of ancestral α, β and γ genes, hence they share sequence similarity. Currently, the trimers are named according to the composition of the α, β and γ chains and more than 15 different laminin isoforms, with various arrangements of laminin subunits, have been identified [3-5]. The first laminin isoform, laminin-111, was discovered more than 30 years ago in the Engelbreth-Holm-Swarm tumor [6]. Subsequently, laminin-211 (composed of α2, β1 and γ1 chains) (Figure 1) was isolated from placenta and was originally called merosin [7]. It is now well established that laminin-211 is the main laminin isoform in skeletal muscle [8,9], and identification of laminin α2 chain mutations in a severe form of congenital muscular dystrophy (merosin-deficient congenital muscular dystrophy; MDC1A) showed the importance of laminin-211 for normal muscle function [10].


Skeletal muscle laminin and MDC1A: pathogenesis and treatment strategies.

Gawlik KI, Durbeej M - Skelet Muscle (2011)

Scheme of laminin-211 heterotrimeric structure. Laminin α2 chain is depicted in red, β1 in green and γ1 in blue. Laminin α2 chain consists of: the N terminal globular domain (LN); tandem rod domains of epidermal growth factor (LEa, LEb, LEc), separating the LN, L4a and L4b globular domains; the laminin coiled-coil (LCC) domain that tangles with the LCC domains of the β1 and γ1 chains; and the C-terminal laminin globular (LG) domains.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3156650&req=5

Figure 1: Scheme of laminin-211 heterotrimeric structure. Laminin α2 chain is depicted in red, β1 in green and γ1 in blue. Laminin α2 chain consists of: the N terminal globular domain (LN); tandem rod domains of epidermal growth factor (LEa, LEb, LEc), separating the LN, L4a and L4b globular domains; the laminin coiled-coil (LCC) domain that tangles with the LCC domains of the β1 and γ1 chains; and the C-terminal laminin globular (LG) domains.
Mentions: The basement membrane is a thin scaffold of specific extracellular protein networks associated with various cell types, including muscle fibers. This specialized framework of extracellular matrix (ECM) provides important functional cues to cells. Laminins comprise a family of glycoproteins that are major components of all basement membranes [1]. Occurrence of a laminin molecule in hydra, one of the oldest multicellular organisms, indicates that laminins existed already 600 million years ago [2]. Laminins are large (400-900 kDa) heterotrimeric molecules composed of one α, one β and one γ subunit in a cruciform or T-shaped appearance. To date, five α, three β and three γ chains have been characterized. They represent the products of distinct genes that evolved by duplication and recombination of ancestral α, β and γ genes, hence they share sequence similarity. Currently, the trimers are named according to the composition of the α, β and γ chains and more than 15 different laminin isoforms, with various arrangements of laminin subunits, have been identified [3-5]. The first laminin isoform, laminin-111, was discovered more than 30 years ago in the Engelbreth-Holm-Swarm tumor [6]. Subsequently, laminin-211 (composed of α2, β1 and γ1 chains) (Figure 1) was isolated from placenta and was originally called merosin [7]. It is now well established that laminin-211 is the main laminin isoform in skeletal muscle [8,9], and identification of laminin α2 chain mutations in a severe form of congenital muscular dystrophy (merosin-deficient congenital muscular dystrophy; MDC1A) showed the importance of laminin-211 for normal muscle function [10].

Bottom Line: By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events.Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death.In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.

ABSTRACT
Laminin-211 is a cell-adhesion molecule that is strongly expressed in the basement membrane of skeletal muscle. By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events. The importance of laminin-211 in skeletal muscle is evident from merosin-deficient congenital muscular dystrophy type 1A (MDC1A), in which absence of the α2 chain of laminin-211 leads to skeletal muscle dysfunction. MDC1A is the commonest form of congenital muscular dystrophy in the European population. Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death. Mice with laminin α2 chain deficiency have analogous phenotypes, and are reliable models for studies of disease mechanisms and potential therapeutic approaches. In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions. We will also discuss the molecular pathogenesis of MDC1A and advances toward the development of treatment.

No MeSH data available.


Related in: MedlinePlus